Focal segmental glomerulosclerosis (FSGS) is characterized by the accumulation of fibrotic proteins in glomeruli, initially affecting only some glomeruli (focal) and affecting only a segmental portion of the affected glomeruli. FSGS includes the follow entities: 1) idiopathic FSGS, including a particularly aggressive collapsing variant; 2) HIV-associated FSGS, and 3) hyperfiltration FSGS associated with reduced nephron mass. The most commonly accepted model of pathogenesis proposes that injury to the podocyte (the visceral glomerular epithelial cell) initiates a process that leads to glomerular scarring. This model is supported by recent findings that familial FSGS can be associated with mutations in podocyte-expressed genes WT-1, actinin 4, and podocin. African-Americans are at a three-fold risk of developing idiopathic FSGS, and at an 18-fold increased risk for HIV-associated FSGS, although most patients lack a family history of FSGS. These observations have suggested a genetic basis for increased susceptibility, but the relevant loci have not been identified. We hypothesize that a gene or genes present in people of African descent, predisposes to FSGS following exposure to particular environmental factors such as infection by parvovirus B19, SV40 or HIV-1. In collaboration with the Kidney Disease Section, NIDDK, a multicenter study with 13 extramural sites has been initiated. We have accrued 236 African-Americans and 114 caucasians with FSGS, 259 intravenous drug users who have been infected with HIV for at least eight years but retain normal kidney function, and 125 normal donor controls. We are using a candidate gene approach to identify markers associated with the FSGS phenotype. In a preliminary analysis, cases and controls have been genotyped for diallelic candidate genes involved in inflammatory response or fibrosis. We have genotyped all patients for one or more polymorphisms at approximately 40 loci, including a number of chemokines and chemokine receptors, cytokines, and components of the renin-angiotensin -TGFb axis. We have observed an association with the Alu insertion allele (I) with increased risk for FSGS in African-Americans. The II genotype was significantly more frequent among black FSGS cases than in unaffected controls. For the Among African-American subjects, the Alu II genotype was more common among FSGS patients compared to HIV-seropositive normal kidney subjects (OR=2.0, p=0.003). Interestingly, for caucasian subjects there was trend in the opposite direction, with the II genotype less frequent among FSGS patients compared with blood donors (OR 0.56, P=0.08). As there are more than 70 identified single nucleotide polymorphisms (SNPs) in the ACE gene, it is not possible to discern if the ins/del is itself affecting the causal pathway of the disease or is tracking through linkage disequilibrium the causal site. We have completed sequencing the ACE gene in 400 FSGS cases and controls to determine haplotype structure, identify SNPs in linkage disequilibrium with the ins/del, and identify the causative haplotype alleles. This study should also provide insight into the role of ACE alleles in hypertension, an important cardiovascular risk factor disproportionately affecting AA. A minor finding was seen in the TGFb1 gene (TGFB1), which is a well recognized pro-fibrotic cytokine [Review reference 19]. The homozygous wild type haplotype (G at -800, C at -509, L at codon 10, and R at codon 25) was more common among African-American HIV-seronegative FSGS subjects compared with blood donors (OR 2.0, P=0.03). There was no similar trend for African-American HIV-associated FSGS patients compared to HIV-seropositive normal kidney subjects.